title: Effect of NSAID administration on tissue levels of immunoreactive prostaglandin E2, leukotriene B4, and (S)-flurbiprofen following extraction of impacted third molars.
abstract: Post-operative pain and inflammation are frequently managed with non-steroidal anti-inflammatory drugs (NSAIDs). Despite the prevalence of their use, however, relatively little is known about in vivo tissue concentrations of inflammatory mediators at the site of tissue injury and their modulation by NSAIDs. This study compares the effect of oral administration of the NSAID flurbiprofen, to placebo, on tissue levels of immunoreactive prostaglandin E2 (iPGE2), leukotriene B4 (iLTB4), and (S)-flurbiprofen within the surgical wound using implanted microdialysis probes in the dental impaction pain model. Twenty-four healthy patients in need of extraction of partial to complete bony mandibular third molars were recruited for this randomized, double-blind, placebo-controlled study. Following pre-operative administration of N2O/O2, midazolam i.v., and regional block anesthesia with 3% mepivacaine, each patient underwent surgical removal of their impacted third molars. Immediately following completion of the surgery, two semi-permeable microdialysis probes (3 kDa molecular weight cut-off) were implanted into each mandibular surgical site. Patients were taken to a recovery room and microdialysis samples and patient pain reports (visual analog scale, VAS) were collected at 30 min intervals for 4 h. Patients randomly received either flurbiprofen (200 mg orally) or placebo at the onset of post-operative pain. Dialysate samples were collected, frozen, and later assayed for iPGE2, iLTB4, and (S)-flurbiprofen levels. Results of this study show that flurbiprofen decreased post-operative pain by approximately 70% compared to placebo-treated patients (P < 0.001). During the 4 h post-operative timecourse of this study, flurbiprofen treatment significantly reduced peak tissue levels of iPGE2 (9.2 +/- 2.6 vs. 0.4 +/- 0.15 nM; P < 0.001), without having a significant effect on peak tissue levels of iLTB4 (2.5 +/- 1.4 vs. 1.49 +/- 0.86 nM) compared to placebo treatment. Levels of (S)-flurbiprofen significantly increased within the surgical wound exceeding therapeutic levels by 60 min after administration. Flurbiprofen is able to significantly suppress the local production of iPGE2 and provide significant analgesic efficacy without altering iLTB4 tissue levels in this model of acute post-operative inflammatory pain. These data indicate that NSAIDs selectively alter eicosanoid levels within surgical wound and evoke analgesia at time points coincident with elevated wound levels of the drug. The combined use of microdialysis probes in awake patients who provide simultaneous pain reports may offer insight into peripheral mechanisms of inflammatory mediator release and pain.
authors.affiliation: Division of Oral and Maxillofacial Surgery, University of Minnesota, School of Dentistry, Minneapolis, MN 55455, USA Department of Oral Science, University of Minnesota, School of Dentistry, Minneapolis, MN 55455, USA Department of Restorative Sciences, University of Minnesota, School of Dentistry, Minneapolis, MN 55455, USA Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Roszkowski
authors.forename: James Q
authors.initials: JQ
authors.lastname: Swift
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Hargreaves
mesh_terms: D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000032:analysis / Q000627:therapeutic use*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000032:analysis / Q000627:therapeutic use*; D015232:Dinoprostone / Q000032:analysis*; D004311:Double-Blind Method; D005480:Flurbiprofen / Q000009:adverse effects / Q000032:analysis / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D007975:Leukotriene B4 / Q000032:analysis*; D017551:Microdialysis; D008964:Molar, Third; D014081:Tooth Extraction; D014095:Tooth, Impacted; D014947:Wounds and Injuries / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007975:Leukotriene B4; D005480:Flurbiprofen; D015232:Dinoprostone